Standard Error Of Mean Research Articles

Helping Us Grow Stronger (HUGS)/Abrazos: a community-based initiative improved perinatal mental health in an urban cohort

Targeted programs aimed at improving maternal mental health, particularly among those exposed to social determinants of health, are increasingly critical since the onset of the COVID-19 pandemic, yet the impact of such programs is poorly understood. This study aimed to evaluate the impact of a novel, language-concordant community-based program on perinatal mental health. We conducted a prospective cohort study of peripartum individuals referred to a new community-based intervention known as Helping Us Grow Stronger (HUGS/Abrazos). Participants received up to 4 remote sessions with a cognitive behavioral therapy trained social worker, up to 3 resource navigation sessions with a community health worker, and direct relief with a grocery gift card and care package. Before and after the program, participants completed validated survey instruments to assess mental health and social determinants of health. A total of 178 participants were assessed after program completion, including 133 who were assessed before and after the program. The cohort was composed of 62.9% Hispanic or Latinx participants with a mean age of 29.8 year (standard error of mean, 0.46). There were high rates of food insecurity (111/178; 62.4%), experiences of discrimination (119/178; 66.9%), and SARS-CoV-2 infection (105/178; 59.0%). The program was associated with statistically significant improvements in the Edinburgh Postnatal Depression scores (baseline [mean±standard error of mean], 8.44±0.55 vs 6.77±0.51 after program completion; P=.0001) and Perceived Stress Scale scores (baseline, 15.2±0.74 vs 14.0±0.71; P=.035). Participants exposed to stressors including food insecurity and experiences of discrimination had higher baseline depression, stress, and anxiety scores. Those with experiences of discrimination, food insecurity, and SARS-CoV-2 infection during pregnancy were more likely to have improvements in mental health scores postintervention. In this diverse urban cohort, a novel community-based intervention was associated with improvements in depressive symptoms, perceived stress, and anxiety, particularly among those with social determinants of health.

Once-Daily Oral Berotralstat for Long-Term Prophylaxis of Hereditary Angioedema: The Open-Label Extension of the APeX-2 Randomized Trial

Berotralstat is a first-line, once-daily oral plasma kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients 12 years or older. This analysis examined the safety and effectiveness of long-term prophylaxis with berotralstat. APeX-2 was a phase 3, parallel-group, multicenter trial in patients with HAE caused by C1-inhibitor deficiency (NCT03485911). Part 1 was a randomized, double-blind, placebo-controlled evaluation of 150 and 110 mg of berotralstat over 24 weeks. In part 2, berotralstat-treated patients continued the same treatment, and placebo-treated patients were re-randomized to 150 or 110 mg of berotralstat for 24 weeks. In part 3, all patients were treated with open-label berotralstat at 150 mg, which could be continued for up to an additional 4 years. In part 3, the primary endpoint was long-term safety and tolerability. Secondary endpoints included HAE attack rates and quality of life (QoL). Eighty-one patients entered part 3. Treatment-emergent adverse events (TEAEs) occurred in 82.7% of patients, with most being mild or moderate in severity. The most common TEAEs were nasopharyngitis, urinary tract infection, abdominal pain, arthralgia, coronavirus infection, and diarrhea. Drug-related TEAEs occurred in 14.8% of patients, but none were serious. For patients who completed 96 weeks of berotralstat treatment (n= 70), the mean (standard error) change in attack rate from baseline was-2.21 (0.20) attacks/mo. Clinically meaningful improvements in QoL were also observed, with the largest improvements in the functioning domain. Berotralstat was generally well tolerated, provided rapid and sustained reductions in HAE attacks and improved QoL over 96 weeks.

LIDAR MATCHING STRATEGIES FOR HD POINT CLOUD MAP GENERATION IN URBAN AREA

Abstract. Autonomous driving relies on high accuracy point vector map, which was generated by the point cloud map, and pre-provides the vehicle preliminary road environment information. Lidar Odometry and Mapping (LOAM) has always been a promising research topic in the field of robotics, environment sensing, and currently autonomous driving. However, in certain urban environments like basement parking lot, tunnels, highways, or other similar settings, the geometric features are not clearly discernible. As a result, algorithms resembling the LOAM framework may encounter difficulties in accurately mapping these areas. The paper utilized relative low-cost LiDAR expecting to propose a state-of-the-art point cloud mapping/update scheme. We compared the GNSS-challenge area with straight line and loop area separately, simultaneously considered the DG, ICP, NDT matching algorithm for the low-cost mapping/update strategy. With the realistic experiment conduction, our result evaluated by point to point corresponding mean error and standard error. For the straight line environment, ICP has the fastest convergence in empirical cumulative distribution under 0.4 meters. For the loop scenario, point-to-point ICP still has the fastest convergence in empirical cumulative distribution under 0.22 meters. Yet both of them still suffer from the fault matching.

Outcomes of the Endoscopic Endonasal Approach for the Treatment of Clival Chordomas: A Single-Center Experience.

Objective Chordoma is a low-grade malignant tumor that originates from the remnant tissue of the embryonic notochord. Postoperative or definitive radiotherapy (RT) has been used to enhance local control. This study aims to assess the outcomes of the expanded endoscopic endonasal approach (EEA) for maximal removal of clival chordomas followed by RT for visualized residual or tumor recurrence. Materials and Methods A retrospective review was performed on consecutive patients with clival chordoma who underwent endoscopic endonasal resection in the otorhinolaryngology and neurosurgery departments, between 2016 and 2021. We included all patients with pathologically confirmed clival chordoma who were treated using the EEA. Patients who underwent combined external and endoscopic approaches or transcranial surgery were excluded. Results Seventeen patients were included in this study. Most of them had tumors located in the middle clivus. Regarding RT, the majority of patients underwent postoperative RT. Almost half of them underwent CyberKnife (CK) RT. None of them had severe toxicities (grade 3 or higher). Three patients died, resulting in a mortality rate of 17.6% none of them related to radiation side effect. The 2-year overall survival was 82.4% (mean standard error [SE] = 1.765, 95% confidence interval [CI] = 1.505-2.024), and the progression-free survival (PFS) was 76.5% (mean SE = 3.403, 95% CI = 2.791-4.016). No distal metastasis was reported in our series. Conclusion This series demonstrates that expanded endoscopic endonasal approach (EEA) for the resection of skull base chordomas, followed by CyberKnife radiosurgery, presents a viable alternative to proton beam therapy; however, further research is necessary to directly compare these modalities.

Evaluation of the neurocognitive and neuroprotective potentials of selected Nigerian medicinal plants in experimental models of dementia

AbstractBackgroundRecent studies have implicated oxidative stress, chronic neuroinflammation, functional cholinergic deficits, and glutamatergic pathway disruptions in the pathophysiology of dementia. However, certain medicinal plants are being used in the management of dementias by the inhabitants of Ibarapa Area of South‐Western Nigeria, hence this study.MethodEthno‐pharmacological survey of medicinal plants used in the management of dementias in Ibarapa Area of Oyo State, South‐Western Nigeria was conducted using semi‐structured questionnaires and open‐ended interviews. Phytochemical, antioxidant, anti‐inflammatory, anti‐nociceptive, and cholinesterase‐inhibiting screenings were conducted on selected medicinal plants (SMPs) using standard assays. Preliminary cytotoxicity screening of promising crude extracts were determined using brine shrimp lethality assay (BSLA). LD50, acute and sub‐chronic administrations of the SMPs into groups of mice were determined using Organization of Economic Cooperation and Development (OECD) 423 guideline. Haematological, biochemical, and histopathological examinations following single and repeated doses of crude extracts of SMPs into groups of mice were determined using standard assays. Behavioural studies using relevant mouse models were conducted. Mechanistic studies using cell lines are being carried out on the promising SMPs. Data are expressed as mean ± standard error of mean (SEM) and analyzed using one‐way analysis of variance (ANOVA) followed by post‐hoc test (Student‐Newman‐Keuls test).ResultThe ethnomedicinal survey revealed about 105 medicinal plants belonging to more than 50 families being used as memory enhancers in the management of dementias by the inhabitants of Ibarapa Area of Oyo State in south‐Western Nigeria. Phoenix dactylifera, Combretum mucranthum, Parquitena nigrescens, Crinum jagus, Blighia sapida, Entandrophragma utile, Ficus exasperate showed significant antioxidant, anti‐inflammatory, and anti‐cholinergic activities. Results of BSLA revealed LC50 values of 100 ‐ 1000 ppm for the screened plants. The oral LD50 values of crude methanol extracts of SMPs are 2000 ‐ 5000 mg/kg. Findings from haematological, biochemical, histological and behavioural assays following both single and repeated administrations of the tested SMPs in mice showed that they are safe and possess promising neurobehavioural potentials that warranted further exploration.ConclusionThe SMPs are safe, highly rich in beneficial phytochemicals, exhibited significant antioxidant, anti‐inflammatory, anti‐cholinesterase, nootropic and neuroprotective potentials thereby suggesting the rationale for their ethnomedicinal use in the management of NNDs.

Evidence from Mendelian randomization: increased risk of miscarriage in patients with asthma.

Several observational studies have revealed a possible association between asthma and miscarriage. However, inferring causal relationships from observational studies may be fraught with problems like bias, reverse causation, and residual confounding. Therefore, to assess the possible causal effect of asthma on miscarriage, we performed a two-sample Mendelian randomization (MR) analysis. Asthma (56,167 cases and 352,255 controls) and miscarriage (9,113 cases and 89,340 controls) data from two GWAS of European ancestrywere evaluated. Single nucleotide polymorphisms (SNPs) were used as instrumental variables (IVs). The random effect inverse-variance weighted (IVW) Mendelian randomization approach was used as the primary method, and MR-Egger, weighted-median, and MR-PRESSO approaches were replenished as sensitivity analysis to test the robustness of the results. In total, 70 SNPs were obtained using the SNP criteria. Additionally, the MR study found substantial evidence of the causalitybetween asthma and miscarriage [IVW, OR=1.092; 95% CI=1.017-1.174; p<0.05]. The sensitivity analysis demonstrated the reliability of the MR findings [horizontal pleiotropy (MR-Egger, intercept=-0.0002; Standard error of mean, se=0.006; p=0.975)]. Asthma is a causal risk factor for miscarriage in European populations, according to MR evidence. Our results emphasize the significance of asthma management in reducing the risk of miscarriage in individuals with asthma.

Morphometrical parameters of acetabulum of hip bone - An osteological study

Background: Acetabulum is an approximately hemispherical cavity on the lateral aspect of the hip bone. Acetabulum is not always of the same shape, size, or depth. Any deviations of the parameters from normal range have strong correlation with the development of various kinds of pathologies. Aims and Objectives: Acetabulum is an approximately hemispherical cavity on the lateral aspect of the hip bone. Acetabulum is not always of the same shape, size or depth. Any deviations of the parameters from normal range have strong correlation with the development of various kinds of pathologies. Materials and Methods: This study was conducted in department of Anatomy, Yenepoya Medical College, Mangalore. Two hundred hip bones were included in the study. Various parameters of the acetabulum were measured. The morphometrical parameters measured were: (a) Transverse diameter of acetabulum, (b) acetabular height, (c) acetabular depth, (d) acetabular volume, (e) distance from pubic tubercle to anterior rim of acetabulum, (f) ratio between distance from pubic tubercle to anterior rim of acetabulum and acetabular height. Range, mean, standard deviation, and standard error of mean were determined for each parameter. P value was also calculated to compare the parameters side wise. Results: The independent T test was done and the P value was calculated for each parameter. Acetabular volume showed a significant difference between left- and right-sided bones. Most of the parameters showed highly significant difference between male and female hip bones in both right side and left side. Conclusion: As total and partial hip replacements are common surgeries performed these days, knowledge of the dimensions of acetabulum will assist prosthetists to construct suitable prosthesis for Indian population. It would be also useful in the fields of anatomy, osteology, and anthropology.

Comparing intra‐individual variability on executive functioning tasks in individuals with Mild Cognitive Impairment and Dementia of the Alzheimer Type: Results from the ARMADA Study

AbstractBackgroundCognitive decline is most often assessed mean group differences on static measures of cognitive abilities (MacDonald et al., 2009). Another, perhaps more dynamic, method to understanding cognitive functioning is to evaluate variability in performance within an individual, termed intraindividual variability (IIV), which has been associated with reduction in gray matter and less efficient cognitive processing. Using results from a multi‐site, longitudinal ARMADA study that validated NIH Toolbox across the cognitive aging spectrum, we investigated whether IIV in reaction time processing can differentiate between older adults with normal cognition, mild cognitive impairment (MCI), or dementia of the Alzheimer type (DAT), as well as the relative magnitude of differences between groups.MethodAs part of the Advancing Reliable Measurement in Alzheimer’s Disease and cognitive Aging study (ARMADA; Weintraub et al 2020), participants completed the NIH Toolbox Cognition Battery, including two measures of executive functioning, Dimensional Change Card Sort and Flanker Inhibitory Control, which include granular reaction time data in milliseconds. We analyzed standard deviation and mean absolute deviation of item‐level data of all trials, correct trials only, and incorrect trials only for three groups: normal controls, those with amnestic MCI, and those with mild DAT.ResultWe observe large effect sizes of reaction time by clinical group, with the mild DAT group demonstrating mean standard error across trials of approximately .5 seconds throughout, compared with .25 seconds for MCI and .10 seconds for the control group (Figure 1). This translates to an approximate 5‐fold increase in processing speed in the most severe clinical group. Examining time trends, we see that while the NC and MCI group were faster as the test progressed; there is no similar learning effect for the mild DAT group. Similar effect sizes were observed for the Flanker test.ConclusionThis study represents one of the first studies to examine clinical performance using process data from two executive functioning measures on the NIH Toolbox across the cognitive aging spectrum. Future work will explore more definitions of IIV to determine which measure will maximally differentiate between established clinical groups and examine longitudinal differences.

Investigation of LSTM Model in Stock Prices Prediction During the COVID-19 Based on Smartphone Brands

The unforeseen outbreak of the COVID-19 pandemic in early 2020 had a profound impact on the real economy and business sectors, leading to a period of heightened volatility. The stock price of smartphone brands had shown an abnormal trend of fluctuation and hard to be predicted by using the inchoate regression and machine learning models. In this paper, Long Short-Term Memory (LSTM) is adapted to predict the stock price of five top smartphone brands. Spanning the period from 2016 to 2021, the dataset for each brand contains 1258 data points, which are split into two groups, training set including 850 observations and test set including 408 observations after the pandemic in 2020. The model employed two prices as x and the next price as y to be predicted. The structure of the model in this work is composed of 3 layers, with 64 and 5 neurons in the first two LSTM layers respectively and a dense layer for dense equal to 1. The model is based on TensorFlow system with Adaptive Moment Estimation optimizer and Mean Absolute Error as the loss function. For the model checking, Root Mean Standard Error, Mean Absolute Error and R-square score are calculated to evaluate the precision of the prediction. Experimental results indicate that under an unexpected external condition, LSTM is effective in stock price prediction to a certain extent. Further investigations are still needed to improve LSTM applied in the stock market.

Clinical Manifestations.

Cognitive decline is most often assessed mean group differences on static measures of cognitive abilities (MacDonald et al., 2009). Another, perhaps more dynamic, method to understanding cognitive functioning is to evaluate variability in performance within an individual, termed intraindividual variability (IIV), which has been associated with reduction in gray matter and less efficient cognitive processing. Using results from a multi-site, longitudinal ARMADA study that validated NIH Toolbox across the cognitive aging spectrum, we investigated whether IIV in reaction time processing can differentiate between older adults with normal cognition, mild cognitive impairment (MCI), or dementia of the Alzheimer type (DAT), as well as the relative magnitude of differences between groups. As part of the Advancing Reliable Measurement in Alzheimer's Disease and cognitive Aging study (ARMADA; Weintraub et al 2020), participants completed the NIH Toolbox Cognition Battery, including two measures of executive functioning, Dimensional Change Card Sort and Flanker Inhibitory Control, which include granular reaction time data in milliseconds. We analyzed standard deviation and mean absolute deviation of item-level data of all trials, correct trials only, and incorrect trials only for three groups: normal controls, those with amnestic MCI, and those with mild DAT. We observe large effect sizes of reaction time by clinical group, with the mild DAT group demonstrating mean standard error across trials of approximately .5 seconds throughout, compared with .25 seconds for MCI and .10 seconds for the control group (Figure 1). This translates to an approximate 5-fold increase in processing speed in the most severe clinical group. Examining time trends, we see that while the NC and MCI group were faster as the test progressed; there is no similar learning effect for the mild DAT group. Similar effect sizes were observed for the Flanker test. This study represents one of the first studies to examine clinical performance using process data from two executive functioning measures on the NIH Toolbox across the cognitive aging spectrum. Future work will explore more definitions of IIV to determine which measure will maximally differentiate between established clinical groups and examine longitudinal differences.

Development and validation of a predictive model for fetal cerebral maturation using ultrasound for fetuses with normal growth and fetal growth restriction.

Investigation of fetal cerebral maturation (FCM) is necessary and important to provide crucial prognostic information for normal and high-risk fetuses. The study aimed to develop a valid and quantitative predictive model for assessing FCM using ultrasound and validate the model for fetuses with normal and restricted growth. This was a multicenter prospective observational study. Fetuses with normal growth recruited from a university teaching hospital (Center 1) and a municipal maternal unit (Center 2) were included in the training set and external validation set 1, respectively. The 124 growth-restricted fetuses enrolled in Center 1 were included in validation set 2. FCM was used to describe the gestational age (GA) in this study. The model was developed based on the sum of fetal cranial parameters (total fetal cranial parameters), including head circumference (HC) and depths of the insula (INS) and sylvian fissure (SF), parieto-occipital fissure (POF), and calcarine fissure (CF). A regression model, constructed based on total fetal cranial parameters and predicted GA, was established using the training set and validated using external validation set 1 and validation set 2. The intra- and interobserver intraclass correlation coefficients for HC, and depths of the INS and SF, POF, and CF were >0.90. An exponential regression equation was used to predict FCM: predicted GA of FCM (weeks) =11.16 × exp (0.003 × total fetal cranial parameters) (P<0.001; adjusted R2=0.973), standard error of estimate, 0.67 weeks. The standard error of the predicted GA of FCM from the model was ±4.7 days. In the validation set 1, the mean standard error of the developed prediction model for FCM was 0.97 weeks. The predictive model showed that FCM was significantly delayed in validation set 2 (2.10±1.31 weeks, P<0.001), considering the GA per the last menstrual period. The predictive performance of the FCM model developed in this study was excellent, and the novel model may be a valuable investigative tool during clinical implementation.

Predicting sulfide precipitation in magma oceans on Earth, Mars and the Moon using machine learning

The sulfur content at sulfide saturation (SCSS) of a silicate melt can regulate the stability of sulfides and, therefore, chalcophile elements’ behaviors in planetary magma oceans. Many studies have reported high-pressure experiments to determine SCSS using either linear or exponential regressions to parameterize the thermodynamics of the system. Although these empirical equations describe the effects of different parameters on SCSS, they perform poorly when predicting laboratory measurements. Here, we compiled 542 published analyses of experiments performed on a range of sulfide and silicate compositions at varying P-T conditions (<24 GPa, <2673 K). Using empirical equations, linear regression, Random Forest algorithms, and a hybrid algorithm employing empirical fits to P-T conditions and the Random Forest algorithm for compositions, we developed several SCSS models and compared them to laboratory measurements. The Random Forest and hybrid models (R2 = 0.82–0.91, mean average error [MAE] < 746 ppmw S, residual mean standard error [RMSE] < 972 ppmw S), significantly outperform previous empirical models (R2 = 0.28–0.69, MAE = 622–1,170 ppmw S, RMSE = 1,070–1,744 ppmw S), whereas linear regression performs moderately well, i.e., between the classic and machine learning models. We applied our hybrid model to predict SCSS during magma ocean solidification on Earth, Mars, and the Moon, and we compared our model results to expected S contents in the residual magma oceans calculated by mass balance. Our results confirm that during early accretion, sulfides precipitated from magma oceans and into the outer cores of Earth and Mars, but not the Moon. Subsequently, once the respective magma oceans began precipitating minerals with increasingly FeO-rich and SiO2-, Al2O3-, and MgO-depleted compositions, the increasing S concentration in the residual magma was offset by temperature and compositional effects on SCSS, preventing sulfide precipitation during intermediate stages of crystallization. Sulfides precipitated late during magma ocean crystallization, but failed to percolate through the underlying crystalline mantle, significantly contributing to the modern bulk-silicate sulfur abundances of Earth, Mars, and the Moon. Our calculations suggest that late-stage sulfide precipitation occurred at shallow depths of 120–220 km, 40–320 km, and < 10 km in the magma oceans of Earth, Mars, and the Moon, respectively.

Healthcare Utilization and Cost of Care Analysis of Patients with Sickle Cell Disease with High Vs. Low Biomarkers: A Retrospective Chart Review

Sickle cell disease (SCD) is a red blood cell (RBC) disorder that is associated with frequent and unpredictable vaso-occlusive episodes (VOEs) including pulmonary hypertension, acute chest syndrome, chronic anemia, priapism, splenic and renal dysfunction, and stoke. The total cost to manage a SCD patient with a life expectancy of 64 years is between $1.3-$2.1M. Within the United States alone, up to 67% of adults have ≥3 VOEs per yearthat accounts for most of the healthcare utilization, including 78% of emergency room (ER) visits and 95% of hospitalizations. Despite the same single gene mutation of beta-globin, the frequency of VOEs amongst patients is highly variable. The pathophysiology of VOEs involves a complex interplay between circulating blood cells and elevated plasma factors that promote abnormal interactions to the vascular endothelium. Nearly a half century ago studies demonstrated RBC adhesion strongly correlates with disease severity however only recently standardized testing has become available to assess adhesion clinically. More specifically, we developed a suite of RBC health biomarkers and deployed our flow adhesion bioassays in our landmark, observational study (ELIPSIS). We established that flow adhesion of whole blood to vascular cell adhesion molecule-1 (FA -WB-VCAM) at baseline stratified SCD patients with severe disease phenotypes and validated the clinical predictive value of FA-WB-VCAM two years post-ELIPSIS. The objective of this study was to determine whether baseline FA-WB-VCAM biomarker levels could predict patients more likely to receive direct healthcare contact (ER visits/hospital admissions) to manage SCD complications. This study was a retrospective assessment of clinical FA-WB-VCAM in individuals with SCD during steady state between January 2020 through March 2023. Flow adhesion assays were performed using pulsatile, shear flow (1.67Hz, 1.0 dyne/cm 2). SCD patients that received at least 3 steady state FA-WB-VCAM biomarker evaluations within 1-year were included in this analysis. Clinical site received an IRB waiver to obtain patient-reported ER visits and hospitalizations during relevant time periods. We calculated a composite adhesion index by averaging baseline FA-WB-VCAM biomarker evaluations and established SCD disease severity by quantifying the number of ER visits and hospital admissions one year after the most recent FA-WB-VCAM biomarker evaluation. The non-parametric Wilcoxon matched pairs signed rank test was used to test the statistical differences between groups. Data are presented as mean ± standard error of mean. A p-value &amp;lt; 0.05 was considered statistically significant. Out of a total of 3939 clinical tests performed, 366 samples were obtained for “baseline” indications. Of these, only 28 samples were analyzed from 9 unique patients who met the study criteria described above. The average flow adhesion of whole blood to VCAM-1 (FA-WB-VCAM) in SCD patients with high adhesion phenotypes (&amp;gt;400 cells/mm 2) was significantly higher than the low/moderate SCD cohort (mean high=603±78 cells/mm 2, mean low/moderate=343±28 cells/mm 2, p=0.02). More important, the high adhesion cohort had more ER visits (11 vs. 5) and hospitalizations (24 vs 9) and significantly higher healthcare costs ($35,871 vs. $13,563). This is the first healthcare cost analysis assessing the relationship between SCD patients stratified by their adhesive phenotype using the standardized, clinical adhesion biomarker FA-WB-VCAM, and healthcare utilization. The previous ELIPSIS study established that baseline FA-WB-VCAM stratifies patients based on their risk of developing self-reported VOCs during a 6-month longitudinal observation period and their risk of higher clinical disease severity in a 2-year follow-up study. Consistent with this data, the current study demonstrated that a cohort of SCD patients with elevated baseline adhesion phenotypes based on FA-WB-VCAM had a greater utilization of healthcare resources (ER visits and hospitalizations) and had a higher cost of care during the retrospective observation period. These data suggest that RBC health as indicated by “baseline” FA-WB-VCAM levels may predict lower health care utilization and costs, and that this biomarker may be a plausible surrogate endpoint to assess the pharmaco-economic impact of SCD-modifying therapies.

Assessment of Novel Erythroid Signaling Pathways Modulating Hydroxyurea-Mediated Reduction of Vaso-Occlusive Adhesive Interactions in Early Precursors of Sickle Red Blood Cells (RBCs)

Sickle cell disease (SCD) affects ~100,000 Americans and millions worldwide, with healthcare costs in the U.S. exceeding $1 billion annually to treat frequent and unpredictable vaso-occlusive episodes (VOEs). In addition to fetal hemoglobin induction, hydroxyurea (HU) reduces the frequency of VOEs by increasing nitric oxide (NO) bioavailability and decreasing adhesion receptor expression and RBC-endothelial interactions. Very late antigen-4 (VLA-4), the best characterized adhesion receptor in SCD, is highly expressed on circulating reticulocytes (immature RBCs) and white blood cells (WBCs) during VOEs and in SCD patients with severe disease phenotypes and, decreased in response to HU therapy. Like other integrins, VLA-4 is functionally regulated by cell signaling pathways to modulate activity and binding affinity to a wide variety of ligands that are elevated in the SCD micro-environment. There is highly intriguing evidence showing HU modulates adhesion by upregulating a NO/cGMP-dependent pathway to decrease adhesion receptor activity however specific mechanisms remain unclear. The objective of this study was to assess rapid cell signaling pathways involved in HU-mediated reduction in VLA-4 binding to endothelial vascular cell adhesion molecule-1 (VCAM-1). Whole blood (WB) was obtained from patients with SCD at benign clinic visits according to IRB-approved protocols. WB density-gradient centrifugation was used to isolate hematopoietic stem cells (HSCs) and WBCs from the buffy coat layer and, a CD71 monoclonal antibody (Ab) coupled with magnetic beads to isolate reticulocytes from the packed RBC layer. HSCs were matured to erythroblasts (EBs) in appropriate cell culture media and flow cytometric analyses assessed purity of blood samples using CD235a (exclusive WBC marker) and CD45 (exclusive RBC marker) Abs . Blood samples were pretreated with and without a therapeutically relevant hydroxyurea concentration (50mcM) followed by perfusion through micro-fluidic channels coated with VCAM-1 during pulsatile, shear flow (1.67Hz, 1.0 dyne/cm 2). Additionally, EBs were treated with HU combined and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1- one (ODQ; NO-dependent guanylate cyclase inhibitor). Adhered cells were quantified to establish an adhesion index. The non-parametric Wilcoxon matched pairs signed rank test was used to test the statistical differences between groups. Data are presented as mean ± standard error of mean. A p-value &amp;lt; 0.05 was considered statistically significant. There was a significant decrease in WB (p=0.01) and reticulocyte (p&amp;lt;0.0001) adhesion to VCAM-1 in HU-treated samples however, there was no effect on WBC (p&amp;gt;0.99) adhesion suggesting reticulocytes reduce the adhesive burden of blood cells in WB adhesion assays and modulation of VLA-4 binding differs in sickle RBCs when compared to WBCs. More recently, preliminary data from my lab demonstrated that EBs pretreated with HU reduces VLA-4 binding to VCAM-1 (from 126.5 ± 29.42 to 109.5 ± 29.09) by cGMP-dependent mechanisms (HU + ODQ; from 109.5 ± 29.09 to 120.2 ± 42.80). Laboratory-based static and flow adhesion assays have been used for decades to describe adhesion in SCD since earlier studies established that sickle RBCs are more adherent than non-sickle blood cells and, adhesion correlates with SCD severity. For example, the adhesion assay described above has been used to demonstrate that VLA-4 binding can stratify SCD patients based on disease severity and predict impending VOEs. Additionally, reticulocyte and HbF levels strongly correlate with VLA-4 binding to VCAM-1 and, VLA-4-mediated adhesion is increased during patient-reported VOEs and decreased in HU-treated SCD patients. This is the first SCD study demonstrating the role of HU in modulating VLA-4 binding to endothelial VCAM-1 through rapid erythroid signaling pathways. There is also compelling evidence involving downregulation of VLA-4 activity/binding affinity through NO/cGMP dependent mechanisms and enhancement of VLA-4 binding by kinase-dependent pathways. HU has also been shown to modulate adhesion by upregulating a NO/cGMP-dependent pathway to decrease adhesion receptor activity. Collectively, these data suggest that VLA-4 mechanisms may be targeted to therapeutically inhibit vaso-occlusive adhesive events that promote VOEs in SCD.

Numerical modeling of the drying behavior of Adlai (Coix lacryma-jobi L.) grain

The study aimed to develop computational fluid dynamics (CFD) models for simulating the drying performance of Adlai grain during convective drying with an air temperature range of 30°C to 60°C at around 10% to 80% relative humidity (RH). Before CFD modeling, the calculation of selected thermophysical properties of Adlai through mathematical modeling of its food constituents and thin-layer drying experiments were conducted. The simulation of heat and mass (moisture) transfer and visualization of moisture and temperature gradients in Adlai grain during drying were carried out using Analysis Systems (Ansys) Student 2020 R2 software package, specifically the Fluent solver. Results showed that the CFD models exhibited good agreement with the actual drying performance of Adlai. The models were validated using three statistical parameters: coefficient of determination (R2), standard error (S), and percent mean deviation modulus (P%). The R2 values ranged from 0.94-0.98; the S values ranged from 0.0018-0.0066; and the P% values ranged from 6.5%-8.68%. Overall, the models were deemed acceptable in estimating the moisture content of Adlai due to high R2 values, low S values, and P% values of less than 10%. The results validate the use of CFD as a reliable method for predicting the drying performance of Adlai, which contributes to the optimization of the drying process, the improved designing of drying systems, and the enhancement of product quality.

Minimum clinically important differences in the Minnesota Living with Heart Failure questionnaire: from a study of heart failure patients treated with integrated Chinese and Western medicine

ObjectiveThe purpose of this study was to estimate the minimum clinically important differences (MCIDs) in the Minnesota Living with Heart Failure questionnaire (MLHFQ), which targeted patients with heart failure treated with integrated Chinese and Western medicine, as a means of helping doctors and patients judge the effectiveness of intervention.MethodsA total of 194 patients with chronic heart failure were recruited from three general hospitals in Beijing. Anchor-based and distribution-based approaches were used to estimate MCID. The anchor was SF-36 item 2 (HT, Health Transition), and the calculation methods included the mean change method, receiver operating characteristic (ROC) curve analysis, and linear regression model. For the distribution-based approaches, 0.2, 0.5, and 0.8 standardized response mean (SRM) values and standard error of measurement (SEM) value of 1 were used.ResultsThe correlation coefficients of the MLHFQ scale information and HT were 0.346–0.583. Different MCIDs were obtained by the mean change method, ROC curve, and linear regression model. The minimum MCID in the physical domain, emotional domain, and total scores were 3.6, 2.0, and 7.4, respectively; the maximum estimates were 9.5, 2.5, and 13.0, respectively; and the average estimates were 5.7, 2.2, and 10.0, respectively. The average estimates were close to the result of the 0.5 SRM or 1 SEM.ConclusionWe established MCIDs in the MLHFQ using anchor-based and distribution-based approaches. It was recommended to round the average estimates of anchor-based approaches up to the nearest whole number for the MCIDs of the MLHFQ physical domain, emotional domain, and total scores. The results were 6.0, 2.0, and 10.0, respectively.

Long-term effectiveness of eptinezumab in patients with migraine and prior preventive treatment failures: extension of a randomized controlled trial

BackgroundEptinezumab demonstrated efficacy in adults with migraine and prior preventive treatment failures in the placebo-controlled phase of the DELIVER clinical trial; its long-term effectiveness in this population has not yet been reported. The objective of this study was to evaluate the long-term effectiveness of eptinezumab in a migraine patient population during the 48-week extension phase of DELIVER.MethodsDELIVER was conducted June 1, 2020 to September 15, 2022. 865 adults with migraine, with documented evidence of 2–4 prior preventive migraine treatment failures and with completion of the 24-week placebo-controlled period of DELIVER received eptinezumab (100 or 300 mg) during the dose-blinded extension, either continuing their randomized dose or, if originally receiving placebo, were randomized 1:1 to an eptinezumab dose (100 or 300 mg). A mixed model for repeated measures was used to evaluate changes from baseline in the number of monthly migraine days (MMDs).ResultsOf 865 patients entering the extension (eptinezumab 100 mg, n = 433; 300 mg, n = 432), 782 (90.4%) completed and 11 (1.3%) discontinued due to an adverse event. Eptinezumab was associated with early and sustained reductions in migraine frequency. Mean MMDs at baseline were approximately 14 days across groups. Mean (standard error) change from baseline in MMDs over the final dosing interval (weeks 61–72) was −6.4 (0.50) with placebo/eptinezumab 100 mg, –7.3 (0.49) with placebo/eptinezumab 300 mg, –7.1 (0.39) with eptinezumab 100 mg, and −7.0 (0.39) with eptinezumab 300 mg. During weeks 61–72, 63–70% of patients demonstrated ≥ 50% reduction in MMDs, and 36–45% demonstrated ≥ 75% reduction. Headache severity and acute medication use reductions, and patient-reported improvements in most bothersome symptom, disease status, quality of life, and work productivity, were observed. Adverse events were generally mild, transient, and similar in frequency/type to previous eptinezumab trials.ConclusionsThe long-term effectiveness and safety/tolerability of eptinezumab in patients with migraine and 2–4 prior preventive treatment failures was demonstrated by high completion rates and migraine-preventive benefits sustained for up to 18 months, implying that eptinezumab is a viable long-term treatment option for patients still seeking successful migraine treatments.Trial registrationClinicalTrials.gov (Identifier: NCT04418765; URL: https://www.clinicaltrials.gov/ct2/show/NCT04418765); EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25).Graphical

Simultaneous, free-breathing, non-contrast 3D whole-heart coronary magnetic resonance angiography and vulnerable plaque imaging in patients with suspected acute coronary syndrome

Abstract Background Coronary artery high-risk plaque identified on cardiovascular magnetic resonance (CMR) is associated with future coronary events, independent of coronary artery luminal stenosis. We have recently developed a 3-dimensional whole-heart free-breathing non-contrast CMR sequence that allows for simultaneous high-resolution visualisation of the coronary arteries and vulnerable plaque on co-registered bright and black blood images (iT2prep-BOOST) with 100% respiratory scan efficiency. Objectives To validate iT2prep-BOOST in patients with non-ST-segment elevation myocardial infarction (NSTEMI) against the reference standard imaging modalities of invasive X-ray coronary angiography and intravascular imaging [optical coherence tomography (OCT)/intravascular ultrasound (IVUS)]. Methods 41 consecutive patients with suspected NSTEMI, based upon clinical history, electrocardiographic changes and positive high-sensitivity troponin assays, were recruited into the study. Invasive coronary angiography ± intravascular imaging was used to classify coronary segments into the following categories: normal, non-culprit and culprit segments; stenosed segments as well as segments with vulnerable plaque features (lipid, calcium, fibroatheroma, thin cap fibroatheroma (TCFA), plaque rupture and thrombus). The highest plaque/myocardial signal intensity ratio (PMR) in each coronary segment was analysed on iT2prep-BOOST. Results The mean iT2prep-BOOST acquisition time was 10.8 ± 1.3 minutes. The mean ± standard error of mean (SEM) PMR of culprit segments was significantly higher than non-culprit segments, which was significantly higher than normal segments (1.01 ± 0.05 vs. 0.67 ± 0.01 vs. 0.35 ± 0.01, P&amp;lt;0.001). Coronary segments with lipid, calcium and fibroatheroma had a significantly higher PMR compared to normal coronary segments (P&amp;lt;0.001) but lower than segments with TCFA, plaque rupture and thrombus (P&amp;lt;0.001). There was a progressive increase in PMR with increasing degree of coronary stenosis (P&amp;lt;0.001). Patients with type 2 diabetes, hypertension, hyperlipidaemia and family history of coronary artery disease had a significantly higher PMR on iT2prep-BOOST (P&amp;lt;0.001, P=0.02, P=0.04 and P=0.02 respectively). Finally, PMR was positively correlated with HbA1c, total cholesterol, non-HDL cholesterol, LDL cholesterol and triglyceride levels (P&amp;lt;0.001, P=0.02, P=0.02, P=0.05 and P=0.05 respectively). Conclusions In summary, the proposed iT2prep-BOOST framework has the potential to simultaneously acquire coronary artery angiography and to differentiate normal segments from non-culprit and culprit plaque segments. Furthermore, PMR is associated with both biochemical and patient related risk factors for coronary artery disease (CAD). The long-term prognostic value of PMR needs to be investigated in a longitudinal multi-centre study of patients with suspected CAD.Figure 1Figures 2 and 3

Ideal cardiovascular health metrics and cardiovascular mortality in patients with renal insufficiency

Abstract Background With high cardiovascular mortality, the benefits of cardiovascular health (CVH) metrics to renal insufficiency populations remain unclear. Objectives To investigate ideal cardiovascular health metrics (ICVHMs) associations with cardiovascular mortality in a renal insufficiency population compared to normal individuals. Methods We analyzed data from the National Health and Nutrition Examination (NHANES) 2007–2018 Survey, with mortality follow-up through December 31st, 2019. We divided 29,682 participants into three groups based on the estimated glomerular filtration rate. CVH was updated in the latest 2022 American Heart Association recommendations. Cox regression analyses based on NHANES data were used to determine associations between ICVHMs and cardiovascular mortality in patients with renal insufficiency. Results In 29,682 participants, the mean (standard error) age ranged from 40.2 (0.2) to 71.6 (0.4) years. When compared with participants with normal renal function, participants with mild renal insufficiency who had ideal CVH reduced their risk of cardiovascular mortality (Hazard Ratio (HR) = 0.34; 95% confidence interval (CI): 0.14–0.81), while the HR for cardiovascular mortality gradually decreased from 1.47 (95% CI: 0.85–2.52) in participants who had ≤ 1 ICVHMs, to 0.30 (95% CI: 0.12–0.77) in those who had ≥ 6 ICVHMs. In participants with renal insufficiency, for each ICVHMs increment, a 25% reduction in cardiovascular mortality risk was observed (95% CI: 0.69–0.82). Conclusions More ICVHMs counteracted renal impairment harm when compared with populations with normal functions, and cardiovascular benefits increased with ICVHMs in patients with renal insufficiency.

Abstract 361: Effect of Percutaneous Ventricular Assisted Device on a Recovery of Myocardial Function in Swine Model With Prolonged Cardiac Arrest

Background: Percutaneous ventricular assist device (pLVAD) support and Transient aortic balloon occlusion (AO) can preserve cerebral and cardiac blood flow during cardiopulmonary resuscitation (CPR), but it remains unclear if pLVAD reduces post-cardiac arrest myocardial dysfunction. Hypothesis: pLVAD support immediately after the return of spontaneous circulation (ROSC) improves early recovery of myocardial function following prolonged cardiac arrest. Aims: Evaluate the association between early post-ROSC pLVAD support and recovery of myocardial function in a swine model of prolonged cardiac arrest. Methods: This is a secondary analysis of a subset of animals that achieved ROSC in a study comparing pLVAD, transient AO or both during CPR after prolonged cardiac arrest. pLVAD, aortic occlusion, or both were initiated after 24 minutes of ventricular fibrillation cardiac arrest (8 min no-flow and 16 min mechanical CPR). AO was discontinued post-ROSC, and pLVAD support or standard care were continued. Beginning 60 minutes post-ROSC, pLVAD support was weaned to &lt;1.0 L/min while maintaining a MAP &gt;70 mmHg, and subsequently removed at 4 hours when feasible. The primary outcome was the recovery of cardiac index (CI) and left ventricular ejection fraction (LVEF) at 4 hours post-ROSC. Data are shown as mean (standard error). Results: Seventeen animals achieved ROSC without complication and were included in this analysis (pLVAD group, n = 11 [8 were removed from pLVAD], and standard care group, n = 6). For the primary outcome, the pLVAD group had significantly higher CI of 4.2(0.3) vs. 3.1(0.4) L/min/m2 (p=0.043) and LVEF 60(3) vs. 49(4) % (p=0.029) at 4 hours after ROSC, respectively, when compared with the standard care group. Focusing on the early period within 60 minutes after ROSC when maximum pLVAD flow was maintained, the pLVAD group had significantly higher coronary perfusion pressure (62[4] vs. 47[5] mmHg, p=0.019), lower LV stroke work index (3.9[3.0] vs. 14.9[4.4] cJ/m2, p=0.043), and lower total pulmonary resistance index (13.2[4.8] vs. 21.5[14.4] Wood Unit, p=0.001). Conclusion: These results suggest that early pLVAD support after ROSC is associated with better recovery myocardial function compared to standard care after prolonged cardiac arrest.